title: Effect of receptor binding domain mutations on receptor binding and transmissibility of avian influenza H5N1 viruses.
abstract: Although H5N1 influenza viruses have been responsible for hundreds of human infections, these avian influenza viruses have not fully adapted to the human host. The lack of sustained transmission in humans may be due, in part, to their avian-like receptor preference. Here, we have introduced receptor binding domain mutations within the hemagglutinin (HA) gene of two H5N1 viruses and evaluated changes in receptor binding specificity by glycan microarray analysis. The impact of these mutations on replication efficiency was assessed in vitro and in vivo. Although certain mutations switched the receptor binding preference of the H5 HA, the rescued mutant viruses displayed reduced replication in vitro and delayed peak virus shedding in ferrets. An improvement in transmission efficiency was not observed with any of the mutants compared to the parental viruses, indicating that alternative molecular changes are required for H5N1 viruses to fully adapt to humans and to acquire pandemic capability.
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control & Prevention, 1600 Clifton Road, MS-G16, Atlanta, GA 30333, USA.
authors.forename: Taronna R
authors.initials: TR
authors.lastname: Maines
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Chen
authors.forename: Neal
authors.initials: N
authors.lastname: Van Hoeven
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
authors.forename: Ola
authors.initials: O
authors.lastname: Blixt
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Belser
authors.forename: Kortney M
authors.initials: KM
authors.lastname: Gustin
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Pearce
authors.forename: Claudia
authors.initials: C
authors.lastname: Pappas
authors.forename: James
authors.initials: J
authors.lastname: Stevens
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
authors.forename: Rahul
authors.initials: R
authors.lastname: Raman
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Katz
authors.forename: Ruben O
authors.initials: RO
authors.lastname: Donis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005289:Ferrets; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D007251:Influenza, Human / Q000378:metabolism / Q000635:transmission* / Q000821:virology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus